Abstract Funds are requested for an Illumina Genome Analyzer IIX and associated Cluster Station to support the ongoing NIH-funded PI-initiated research programs in the Functional Genomics Core of the Institute for Diabetes, Obesity, and Metabolism (IDOM) as well as the new Epigenomics Program at the University of Pennsylvania School of Medicine. These are very exciting programs, linked by the recognition that environmental factors, including diet and lifestyle, influence the development of diabetes and obesity phenotypes via epigenetic regulation of gene expression. The Functional Genomics Core has already established an ultra- high throughput sequencing capability, supported by institutional funds. With the success and productivity of the nine major investigators focused on epigenomics and gene expression, including the PI and new senior recruits to the University of Pennsylvania, the demand on the current instrumentation is so great that users must wait 4-6 weeks for their samples to be analyzed, even with the instrument running non-stop. The current and future studies of genome-wide transcription factor binding, epigenetic mapping, microRNA discovery, and re- sequencing of candidate human disease regions are critical for the rapid progress we are making, and the proposed acquisition of a second Illumina Genome Analyzer IIX will allow us keep up with the increased demand. The University of Pennsylvania School of Medicine has made a major financial commitment towards this effort, including the funding of equipment and service contract costs not covered by this proposal as well as the staff of the Functional Genomics Core, which is itself a key component of Penn's NIDDK-funded Diabetes and Endocrinology Research Center. In addition, the institution has allocated dedicated space to house the instrument and its associated hardware in the new Fisher Translational Research Building, where the Functional Genomics Core, IDOM, and Epigenomics Program will be co- located. The School of Medicine has also provided a large server room and the required ultra- high speed connections for data storage and access. Scientific oversight will be accomplished by a committee comprised of the PI of the proposal, the IDOM director, and two faculty representatives from the user group. Thus, the Illumina Genome Analyzer will be highly utilized by outstanding, well-funded investigators focused on epigenomic and genomic research with the potential to have a critical impact on major diseases, including diabetes and obesity.